TY - JOUR
T1 - Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast
AU - Gibney, Patrick A.
AU - Schieler, Ariel
AU - Chen, Jonathan C.
AU - Bacha-Hummel, Jessie M.
AU - Botstein, Maxim
AU - Volpe, Matthew
AU - Silverman, Sanford J.
AU - Xu, Yifan
AU - Bennett, Bryson D.
AU - Rabinowitz, Joshua D.
AU - Botstein, David
AU - Drubin, David G.
N1 - Publisher Copyright:
© 2018 Gibney et al.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote Saccharomyces cerevisiae, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar-phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.
AB - Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote Saccharomyces cerevisiae, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar-phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.
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U2 - 10.1091/mbc.E17-11-0666
DO - 10.1091/mbc.E17-11-0666
M3 - Article
C2 - 29444955
AN - SCOPUS:85046450815
SN - 1059-1524
VL - 29
SP - 897
EP - 910
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 8
ER -